Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation

Abstract

• Donor T-Rapa cells were composed of Th1 and Th2 effectors with a reproducible gene expression profile.• Preemptive T-Rapa donor lymphocyte infusion was safe and associated with donor engraftment without excessive GVHD.In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4 1T cells of increased in vivo efficacy that facilitated engraftment and permitted graftversus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4 1 Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4 1 Th2 and Th1 cells relative to regulatory T cells and CD8 1 T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84 months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens. This trial was registered at www.cancer.gov/clinicaltrials as #NCT 00077480. (Blood. 2013;121(15):2864-2874

Low blood lymphocyte count at 30 days post transplant predicts worse acute GVHD and survival but not relapse in a large retrospective cohort

“…Cellular therapy interventions that might ameliorate the increased GVHD associated with low ALC30 include post-transplant infusions of rapamycin-resistant CD4 T-cells (enriched for regulatory T cells) or NK-cell DLI, both of which have the potential to maintain the GVL effect while limiting aGVHD. [47][48][49] Further studies are needed to define the critical cell phenotype of ALC30 and to better define the mechanism by which high ALC30 protects AHSCT recipients from aGVHD and NRM, thereby improving transplant outcomes. Also adjusted for donor gender, donor CMV status, recipient gender, recipient CMV status, relapse risk, intensity and any blank cells (also NS).…”

Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation

“…39 Nonantigen-specific approaches include culturing donor lymphocytes in sirolimus in an effort to change the functional properties of the donor lymphocytes. 40 Antigen-specific approaches to T-cell therapy have been developed to treat virus-associated malignancies after alloHSCT 41,42 and to target minor histocompatibility antigens. 43 Lymphocytes were collected from a single patient with acute lymphoblastic leukemia persisting after allogeneic cord blood transplantation, genetically modified to express an anti-CD19 CAR, and reinfused to treat the acute lymphoblastic leukemia after the patient had received chemotherapy.…”

New strategies of DLI in the management of relapse of hematological malignancies after allogeneic hematopoietic SCT

“…Eighteen of fourty patients (45%) remain in sustained CR at 7-year follow-up. 66 To reduce the risk of relapse after HSCT, Horn et al 67 prospectively studied post-transplant chimerismbased immunotherapyusing fast withdrawal of immunosuppression and DLI in children with early post-transplant mixed chimerism. Patients with mixed chimerism undergoing immunotherapy had similar 2-year EFS compared with patients who achieved full donor chimerism (FDC) spontaneously.…”